B. Joseph Guglielmo

Lipid Formulations of Amphotericin B: Clinical Efficacy and Toxicities

Commercially available lipid formulations of amphotericin B (Abelcet, Amphotec, and AmBisome) represent a significant advance in drug delivery technology. Differences in biochemical, pharmacokinetic, and pharmacodynamic properties among the lipid products have been shown in in vitro and in vivo models. Clinical experience with these products has been primarily in patients either refractory to or intolerant of conventional amphotericin B deoxycholate (AmBd). None of the lipid-based products demonstrates superior efficacy when prospectively compared with AmBd in the treatment of documented infections. When used for the empirical treatment of febrile neutropenia, AmBisome significantly reduced the incidence of proven emergent fungal infections but did not improve short-term survival rates, in comparison with AmBd. Acute infusion-related adverse events vary, whereas nephrotoxicity is reduced with all three lipid formulations. Until superior efficacy is clearly shown (for documented infections) or pharmacoeconomic analyses document the value of these drugs, use of such expensive agents should be highly restricted to those who are intolerant of or refractory to AmBd.

Antimicrobial Selection for Hospitalized Patients with Presumed Community-Acquired Pneumonia: A Survey of Nonteaching US Community Hospitals

OBJECTIVE: To describe and evaluate empiric antimicrobial regimens chosen for hospitalized patients with presumed community-acquired pneumonia (CAP) in US hospitals, including compliance with the American Thoracic Society (ATS) guidelines. Secondary outcomes included length of stay (LOS) and mortality associated with the choice of therapy. METHODS: A nonrandomized, prospective, observational study was performed in 72 nonteaching hospitals affiliated with a national group purchasing organization. Patients with an admission diagnosis of physician-presumed CAP and an X-ray taken within 72 hours of admission were eligible for the study. Demographic, antibiotic selection, and outcomes data were collected prospectively from patient charts. RESULTS: 3035 patients were enrolled; 2963 were eligible for analysis. Compliance with the ATS guidelines was 81% in patients with nonsevere CAP. The most common antibiotic regimen used for empiric treatment was ceftriaxone alone or in combination with a macrolide (42%). The overall mortality rate was 5.5%. The addition of a macrolide to either a second- or third-generation cephalosporin or a β-lactam/β-lactamase inhibitor was associated with decreased mortality and reduced LOS. CONCLUSIONS: Most hospitalized patients with CAP receive antimicrobial therapy consistent with the ATS guidelines. The addition of a macrolide may be associated with improved patient outcomes.

Current recommended dosing of vancomycin for children with invasive methicillin-resistant Staphylococcus aureus infections is inadequate.

Background: Vancomycin area-under-the-concentration-time-curve (AUC) for 24 hours divided by the minimum inhibitory concentration (MIC) (AUC24/MIC) >400 optimally treats invasive methicillin-resistant Staphylococcus aureus (MRSA) infections in adults. It is unknown whether recommended vancomycin dosing regimens for children achieve this value. Methods: AUC24/MIC was calculated in children using vancomycin doses of 40 and 60 mg/kg/d. AUC24 was calculated as daily dose/vancomycin clearance. Vancomycin clearance in children was estimated by 2 approaches: (1) previously literature-reported vancomycin clearance, and (2) calculated vancomycin clearance using previously derived predictor models and a hypothetical population of healthy children. Representative MIC of hospital MRSA isolates was used (0.5, 1.0, and 2.0 μg/mL). Results: The MIC50/90 for pediatric MRSA isolates in the previous year was 1.0 μg/mL. With a dose of 40 mg/kg/d, both approaches consistently predicted AUC24/MIC <400 when MIC was 1.0 μg/mL. At 60 mg/kg/d, AUC24/MIC >400 was more readily achieved when MIC was 1.0 μg/mL, however, an MIC of 2.0 μg/mL resulted in AUC24/MIC <400 for both dosing regimens. Conclusions: A vancomycin dose of 40 mg/kg/d in children is unlikely to achieve the recommended pharmacodynamic target of AUC24/MIC >400 for invasive MRSA infections even when MIC is 1.0 μg/mL. A starting dose of 60 mg/kg/d should be used in settings where isolates with MIC of 1.0 are common. Alternatives to vancomycin should strongly be considered for patients with MIC ≥2.0 μg/mL.

In-Vitro Activity of Miltefosine and Voriconazole on Clinical Isolates of Free-Living Amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri

ABSTRACT. The anticancer agent miltefosine and the antifungal drug voriconazole were tested in vitro against Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. All three amebas are etiologic agents of chronic (Balamuthia, Acanthamoeba) or fulminant (Naegleria) encephalitides in humans and animals and, in the case of Acanthamoeba, amebic keratitis. Balamuthia exposed to <40 μm concentrations of miltefosine survived, while concentrations of ≥40 μM were generally amebacidal, with variation in sensitivity between strains. At amebastatic drug concentrations, recovery from drug effects could take as long as 2 weeks. Acanthamoeba spp. recovered from exposure to 40 μM, but not 80 μM miltefosin. Attempts to define more narrowly the minimal inhibitory (MIC) and minimal amebacidal concentrations (MAC) for Balamuthia and Acanthamoeba were difficult due to persistence of non‐proliferating trophic amebas in the medium. For N. fowleri, 40 and 55 μM were the MIC and MAC, respectively, with no trophic amebas seen at the MAC. Voriconazole had little or no inhibitory effect on Balamuthia at concentrations up to 40 μg/ml, but had a strong inhibitory effect upon Acanthamoeba spp. and N. fowleri at all drug concentrations through 40 μg/ml. Following transfer to drug‐free medium, Acanthamoeba polyphaga recovered within a period of 2 weeks; N. fowleri amebas recovered from exposure to 1 μg/ml, but not from higher concentrations. All testing was done on trophic amebas; drug sensitivities of cysts were not examined. Miltefosine and voriconazole are potentially useful drugs for treatment of free‐living amebic infections, though sensitivities differ between genera, species, and strains.

Risk Factors for Community-Acquired Ciprofloxacin-Resistant Escherichia Coli Urinary Tract Infection

BACKGROUND: Fluoroquinolones are recommended for the empiric treatment of urinary tract infection (UTI) in communities in which uropathogen resistance to trimethoprim/sulfamethoxazole (TMP/SMX) is ≥10% to 20%. However, recent studies also have demonstrated an increase in the isolation of fluoroquinolone-resistant Escherichia coli. Identification of outpatients at increased risk for fluoroquinolone resistance would improve the selection of empiric treatment. OBJECTIVE: To identify risk factors for community-acquired UTIs due to ciprofloxacin-resistant E. coli (CREC). METHODS: All medical records from the University of California at San Francisco Medical Center from January to December 2001 were retrospectively reviewed to identify patients with community-acquired UTI due to CREC. Patients with community-acquired UTI due to ciprofloxacin-susceptible E. coli presenting during the same time period were randomly selected as the study group in a 1:2 ratio of case to controls. RESULTS: Independent risk factors for CREC included recurrent UTI (OR 8.13) and prior exposure to fluoroquinolones (OR 30.35). CONCLUSIONS: Fluoroquinolones continue to be appropriate empiric treatment in most patients with uncomplicated UTI. Nitrofurantoin or a cephalosporin may be better choices in patients with recurrent lower UTI and/or previous fluoroquinolone use.

The FDA extended warning for intravenous haloperidol and torsades de pointes: How should institutions respond?†

BACKGROUND In September 2007, the Food and Drug Administration (FDA) strengthened label warnings for intravenous (IV) haloperidol regarding QT prolongation (QTP) and torsades de pointes (TdP) in response to adverse event reports. Considering the widespread use of IV haloperidol in the management of acute delirium, the specific FDA recommendation of continuous electrocardiogram (ECG) monitoring in this setting has been associated with some controversy. We reviewed the evidence for the FDA warning and provide a potential medical center response to this warning. METHODS Cases of intravenous haloperidol-related QTP/TdP were identified by searching PubMed, EMBASE, and Scopus databases (January 1823 to April 2009) and all FDA MedWatch reports of haloperidol-associated adverse events (November 1997 to April 2008). RESULTS A total of 70 of IV haloperidol-associated QTP and/or TdP were identified. There were 54 reports of TdP; 42 of these events were reportedly preceded by QTP. When post-event QTc data were reported, QTc was prolonged >450 msec in 96% of cases. Three patients experienced sudden cardiac arrest. Sixty-eight patients (97%) had additional risk factors for TdP/prolonged QT, most commonly receipt of concomitant proarrhythmic agents. Patients experiencing TdP received a cumulative dose of 5 mg to 645 mg, patients with QTP alone received a cumulative dose of 2 mg to 1540 mg. CONCLUSIONS While administration of IV haloperidol can be associated with QTP/TdP, this complication most often took place in the setting of concomitant risk factors. Importantly, the available data suggest that a total cumulative dose of IV haloperidol of <2 mg can safely be administered without ongoing electrocardiographic monitoring in patients without concomitant risk factors.

Systematic review of medication safety assessment methods.

PURPOSE The accuracy, efficiency, and efficacy of four commonly recommended medication safety assessment methodologies were systematically reviewed. METHODS Medical literature databases were systematically searched for any comparative study conducted between January 2000 and October 2009 in which at least two of the four methodologies-incident report review, direct observation, chart review, and trigger tool-were compared with one another. Any study that compared two or more methodologies for quantitative accuracy (adequacy of the assessment of medication errors and adverse drug events) efficiency (effort and cost), and efficacy and that provided numerical data was included in the analysis. RESULTS Twenty-eight studies were included in this review. Of these, 22 compared two of the methodologies, and 6 compared three methods. Direct observation identified the greatest number of reports of drug-related problems (DRPs), while incident report review identified the fewest. However, incident report review generally showed a higher specificity compared to the other methods and most effectively captured severe DRPs. In contrast, the sensitivity of incident report review was lower when compared with trigger tool. While trigger tool was the least labor-intensive of the four methodologies, incident report review appeared to be the least expensive, but only when linked with concomitant automated reporting systems and targeted follow-up. CONCLUSION All four medication safety assessment techniques-incident report review, chart review, direct observation, and trigger tool-have different strengths and weaknesses. Overlap between different methods in identifying DRPs is minimal. While trigger tool appeared to be the most effective and labor-efficient method, incident report review best identified high-severity DRPs.

Desired vancomycin trough serum concentration for treating invasive methicillin-resistant staphylococcal infections

Vancomycin area under the curve/minimal inhibitory concentration (AUC/MIC) >400 best predicts the outcome when treating invasive methicillin-resistant Staphylococcus aureus infection; however, trough serum concentrations are used clinically to assess the appropriateness of dosing. We used pharmacokinetic modeling and simulation to examine the relationship between vancomycin trough values and AUC/MIC in children receiving vancomycin 15 mg/kg every 6 hours and methicillin-resistant Staphylococcus aureus MIC of 1 &mgr;g/mL. A trough of 7–10 &mgr;g/mL predicted achievement of AUC/MIC >400 in >90% of children.

Iodine Toxicity in a Patient Treated by Continuous Povidone-Iodine Mediastinal Irrigation

Continuous povidone-iodine irrigation is frequently used to treat mediastinitis after median sternotomy and has been considered safe and effective. We describe a 34-month-old patient with mediastinitis after median sternotomy who was treated with continuous povidone-iodine irrigation and who absorbed toxic quantities of iodine (total serum iodine, 9,375 micrograms/dl; normal range, 4.5 to 9.0 micrograms/dl). An unexplained metabolic acidosis developed, along with changes in mental status, and the patient died. This experience and a thorough review of the literature lead us to believe that continuous povidone-iodine irrigation of the mediastinum is contraindicated.

Dose-response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation

Brain arteriovenous malformations (BAVMs) are a potentially life-threatening disorder. Matrix metalloproteinase (MMP)-9 activity was greatly increased in BAVM tissue specimens. Doxycycline was shown to decrease cerebral MMP-9 activities and angiogenesis induced by vascular endothelial growth factor (VEGF). In the present study, we determined the dose-response effects of doxycycline and minocycline on cerebral MMP-9 using our mouse model with VEGF focal hyperstimulation delivered with adenoviral vector (AdVEGF) in the brain. Mice were treated with doxycycline or minocycline, respectively, at 1, 5, 10, 30, 50, or 100 mg/kg/day through drinking water for 1 week. Our results have shown that MMP-9 messenger ribonucleic acid (mRNA) expression was inhibited by doxycycline starting at 10 mg/kg/day (P < 0.02). Minocycline showed more potent inhibition on MMP-9 mRNA expression, starting at 1 (P < 0.005) and further at more than 30 (P < 0.001) mg/kg/day. At the enzymatic activity level, doxycycline started to suppress MMP-9 activity at 5 mg/kg/day (P < 0.001), while minocycline had an effect at a lower dose, 1 mg/kg/day (P < 0.02). The inhibition of cerebral MMP-9 mRNA and activity were highly correlated with drug levels in the brain tissue. We also assessed the potential relevant signaling pathway in vitro to elucidate the mechanisms underlying the MMP-9 inhibition by tetracyclines. In vitro, minocycline, but not doxycycline, inhibits MMP-9, at least in part, via the extracellular signaling-related kinase 1/2 (ERK1/2)-mediated pathway. This study provided the evidence that the tetracyclines inhibit stimulated cerebral MMP-9 at multiple levels and are effective at very low doses, offering great potential for therapeutic use.